The present invention relates to novel ascorbic acid derivatives and their synthetic method represented by the following general formula (I). 
wherein R1 and R2 are different from each other and independently H or xe2x80x94CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)nxe2x80x94OR3, wherein n is an integer from 2 to 400; and R3 is a lower alkyl group having 1 to 10 carbon atoms.
L-ascorbic acid is one of the most potent compounds causing as an antioxidant in biological systems by scavenging active oxygen species and free radicals.
L-ascorbic acid is a well-known water-soluble antioxidant that has a whitening effect and serves as a cofactor of prolinehydroxylase to promote synthesis of collagen (see. Quaglino, D. Jr., et al., J. Biol. Chem, p272-345, 1997).
L-ascorbic acid is also used in various products requiring a long-term antioxidation effect. But, its usefulness for such products is not so reliable because it is susceptible to heat, light and air.
As such, many studies have been made on the development of ascorbic acid derivatives with enhanced stability while maintaining the antioxidation activity. Notably, a common way to improve the stability of L-ascorbic acid is converting a 2 - or 3-hydroxyl group of L-ascorbic acid to another substituent (see. U.S. Pat. Nos. 5,143,648; 4,780,549; and 4,177,445, Japanese Patent Sho 52-18191, and Korean Patent No. 91-8733).
L-ascorbic acid, which is a water-soluble antioxidant, is almost insoluble in oil and fat (e.g., salad oil and lard oil). Thus, there is a need of developing ascorbic acid derivatives that have a relatively high solubility in both water and organic solvents, for various use as an antioxidant in foods and cosmetics.
Examples of commercially available derivatives of vitamin C include L-ascorbic acid-6-palmitate, 2,6-dipalmitate, 6-stearate, L-ascorbic acid-3-O-ethyl and magnesium L-ascorbic acid-2-phosphate (see. Korean Patent No. 91-8733, and U.S. Pat. Nos. 5,143,648; and 7,179,445).
Among these compounds, relatively fat-soluble derivatives of ascorbic acid are L-ascorbic acid-6-palmitate, 2,6-dipalmitate and 6-stearate. Despite the improved chemical stability, these derivatives still have a limitation in lasting their anti-oxidative activity because of their rapid decomposition in vitro.
In an attempt to overcome these problems, the inventors of this invention derive novel ascorbic acid derivatives having considerably high solubilities in both water and organic solvents due to a polyethylene glycol moiety introduced at the 2 - or 3-hydroxyl group of L-ascorbic acid. The invention also includes a novel ascorbic acid derivative having high stability and long-lasting anti-oxidation effect.
DISCLOSURE OF INVENTION
The present invention relates to a new stable ascorbic acid.
It is therefore an object of the present invention is to provide a novel ascorbic acid derivative that overcomes the drawbacks of the related art methods.
The invention has solved the problems by introducing a polyethylene glycol moiety at the 2 - or 3-hydroxyl group of L-ascorbic acid. The invention is also directed to an ascorbic acid derivative having a high solubility in both water and most organic solvents and an inhibitory activity against tyrosinase.
It is another object of the present invention to provide a method for preparing such an ascorbic acid derivatives.
To achieve the above object, there is provided a novel ascorbic acid derivative by the formula (I) and a method for preparing the same: 
wherein R1 and R2 are independently H or xe2x80x94CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)nxe2x80x94OR3, wherein n is an integer from 2 to 400; and R3 is a lower alkyl group having 1 to 10 carbon atoms.
There is also provided a method for preparing an ascorbic acid derivative represented by the formula (I), wherein R1 represents xe2x80x94CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)nxe2x80x94OR3, wherein n and R3 are defined as above. The method includes: (i) reacting cesium ascorbate represented by the formula (V) with a derivative of polyethylene glycol represented by the formula (IV) in an appropriate solvent, 
wherein R3 is a lower alkyl group having 1 to 10 carbon atoms; n is an integer from 2 to 400; and X is a halogen atom such Cl, Br and I, or sulfonate such as tosylate, triflate or tresylate.
There is also provided a method for preparing a ascorbic acid derivative represented by the formula (I), wherein R1 is a hydrogen atom and R2 represents xe2x80x94CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)nOR3, wherein n and R3 are defined as above. More specifically, according to Scheme 1, the method includes: (i) reacting the compound of the formula (V) with benzyl bromide in the presence of a solvent to form 3-O-benzyl ascorbic acid represented by the formula (VI); (ii) reacting 3-O-benzyl ascorbic acid of the formula (VI) with PEG-I in the presence of cesium carbonate in a solvent to form 3-O-benzyl-2-polyethyleneglycolyl-ascorbic acid represented by the formula (VII); and (iii) hydrogenating the compound of the formula (VII) in the presence of a catalyst. 
wherein Bn is benzyl group; and PEG is CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)nxe2x80x94OR3, wherein n and R3 are defined as above.
Furthermore, a method for preparing a compound of the formula (I) includes: (i) reacting a compound represented by the formula (VIII) with a derivative of polyethylene glycol represented by the formula (IV) in the presence of a base in a solvent; and (ii) hydrolyzing the product in the presence of an acid catalyst, 
wherein R4 and R5 are the same or different and independently hydrogen atom, methyl group, ethyl group, or xe2x80x94CH2)m bonded to R4 and R5, wherein m is 4 or 5; and R6 is hydrogen atom, benzyl group or paramethoxybenzyl group.
Hereinafter, the present invention will be described in further detail.
The invention relates to an ascorbic acid derivative which stability is improved by introducing of polyethylene glycol group at the 2 - or 3-hydroxyl group of ascorbic acid.
The novel ascorbic acid derivative can be prepared by two methods: (1) the one method involves preparing a 5,6-O-acetal or ketal of ascorbic acid, introducing a polyethylene glycol group at the 3-OH position of the protected ascorbic acid in the presence of a base, and then eliminating the acetal or ketal group; and (2) the other method involves direct coupling of non-protected ascorbic acid with a polyethoxylated intermediate.
In the first method, in which the final product is obtained from non-protected ascorbic acid, cesium ascorbate represented by the formula (V) reacts with a derivative of polyethylene glycol represented by the formula (IV) in a suitable solvent to produce the compound represented by the formula (II). 
wherein PEG is xe2x80x94CH2CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94O) nOR3, wherein n and R3 are defined as above; 
wherein R3 is a lower alkyl group having 1 to 10 carbon atoms; n is an integer from 2 to 400; and X is a halogen atom (e.g., Cl, Br or I) or sulfonate (e.g., tosylate, triflate or tresylate). 
The compound represented by the formula (IV) is denoted by PEGnxe2x80x94X.
The solvent used in this reaction is selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethyl phosphoramide (HMPA), N-methylpyrrolidone, pyrrolidone, dimethylacetamide (DMAC), 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and mixtures thereof.
The compound of the formula (V) as used herein is prepared by reacting ascorbic acid with cesium carbonate in water as a solvent and crystallzing the crude cesium ascorbate in isopropyl alcohol.
In the second method, the final product is obtained from non-protected ascorbic acid, the compound represented by the formula (V) reacts with benzyl bromide in a solvent to give 3-O-benzyl ascorbic acid represented by the formula (VI) and then the compound of formula (VI) is coupled with PEG-I in the presence of cesium carbonate, followed by catalytic hydrogenation, to give a compound represented by the formula (III).
The solvent used in the above reaction is selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethyl phosphoramide (HMPA), N-methylpyrrolidone, pyrrolidone, dimethylacetamide (DMAC), 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and mixtures thereof.
Another method for preparing a compound represented by the formula (I) involves synthesizing a 5,6-O-acetal or ketal of ascorbic acid , introducing a PEG group at the 3-hydroxyl position of ascorbic acid and eliminating the acetal or ketal group. More particularly, an ascorbic acid derivative represented by the formula (II) is prepared as follows.
First, a 5,6-O-acetal or ketal ascorbic acid derivative represented by the formula (IX) reacts with a derivative of polyethylene glycol represented by the formula (IV) in the presence of a base in a suitable solvent to produce a compound represented by the formula (X).
Subsequently, an acetal or ketal group of the compound of the formula (X), is eliminated in the presence of an acid catalyst to obtain an ascorbic acid derivative represented by the formula (II): 
wherein R4 and R5 are defined as above; and 
wherein R4, R5 and PEG are defined as above.
Preferably, a derivative of polyethylene glycol represented by the formula (IV) has a molecular weight of from 50 to 20000, more preferably, 300 to 1000. Examples of the alkyl group denoted by R3 in the formula (IX) include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-methyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-desyl. Examples of the said halogen atom include chlorine, bromine and iodine, and examples of sulfonate include tosylate, triflate and tresylate.
To prepare the compound of the formula (X), the 5,6-O-acetal or ketal ascorbic acid derivative represented by the formula (IX) is subjected to coupling reaction with the compound of the formula (IV) in the presence of a suitable base. Examples of the said base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesiun carbonate and sodium hydride. Examples of the suitable solvent include dimethylformamide, dimethylsulfoxide, hexamethyl phosphoramide, N-methylpyrrolidone, pyrrolidone and dimethylacetamide. Preferably, the reaction temperature is from 10 to 90xc2x0 C. and the reaction time is from 1 to 24 hours.
The compound of the formula (X), obtained from O-alkylation at 3-position of the 5,6-acetal or ketal ascorbic acid derivative, is hydrolyzed to eliminate an acetal or ketal group present at hydroxyl groups at 5 - and 6-positions of ascorbic acid, followed by appropriate isolation and purification. The resulting compound is polyethoxylated ascorbic acid represented by the formula (II).
The above hydrolysis reaction is performed in the presence of an acid catalyst, the examples of the said catalyst include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid and acetic acid. Examples of the solvent include methanol, ethanol, methylene chloride, 1,2-methoxyethane and tetrahydrofuran. Preferably, the reaction temperature is from 0 to 70xc2x0 C. and the reaction time is from 1 to 12 hours.
Alternatively, a ascorbic acid derivative represented by the formula (III) can be prepared by synthesizing 5,6-O-acetal or ketal of ascorbic acid, introducing PEG group at the 3-hydroxyl position of ascorbic acid, and eliminating the acetal or ketal. This method is analogous to the above-stated preparing method for an ascorbic acid derivative represented by the formula (II). More specifically, the compound of the formula (XI) reacts with a derivative of polyethylene glycol represented by the formula (IV) in the presence of a base to produce a compound of the formula (XII), followed by catalytic hydrogenation, to give a compound of the formula (XIII). This compound is then hydrolyzed to produce a compound represented by the formula (III): 
wherein R4 and R5 are defined as above; and R8 is benzyl or paramethoxybenzyl group; 
wherein R4, R5, R8 and PEG are defined as above. 
wherein R4, R5, and PEG are defined as above.
The compound of the formula (XI) is obtained by selectively introducing at the 3-hydroxy position of an ascorbic acid with benzyl or paramethoxybenzyl group that can be easily removed through catalytic reduction. To enhance the selectivity of benzylation, the selection of an appropriate solvent and reaction temperature is of importance. Examples of the solvent include dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone,. methylethylketone, acetone, methanol and tetrahydrofuran.
Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium t-butylalkoxide. Preferably, the reaction temperature is from 5 to 50xc2x0 C. and the reaction time is about from 1 to 12 hours.
To prepare a compound of the formula (XII), a compound of the formula (XI) is coupled with a compound of the formula (IV) in the presence of a suitable base. Examples of the said base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride.
The resulting compound of the formula (XII) is reduced into a compound represented by the formula (XIII), which is then hydrolyzed to give a compound represented by the formula (III).
The above hydrolysis reaction is performed in the presence of an acid catalyst, the examples of the said catalyst include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid and acetic acid. Examples of the solvent used for the hydrolysis include methanol, ethanol, methylene chloride, 1,2-methoxyethane and tetrahydrofuran. Preferably, the reaction temperature is from 0 to 70xc2x0 C. and the reaction time is from 1 to 12 hours.
The reduction is performed in the presence of a catalyst, e.g., palladium, palladium-carbon, platinum black and platinum oxide in an organic solvent, e.g., methanol, ethanol and ethylacetate.